Richard Lehman’s journal review—28 May 2013

May 28, 2013

JAMA 22 May 2013 Vol 309
2105 Viewpoints carry with them an offer of agreement or disagreement, and everything I write in these columns is based on that. I hope you sometimes click on the links, and I often wish you would disagree with me more. I hope the same goes for the authors of this Viewpoint piece about Medication Nonadherence: a Diagnosable and Treatable Medical Condition, but they sound almost angrily in earnest. “To further improve the diagnostic accuracy of the problem, attention should be paid to the underlying behavior(s) at hand. There are at least six representative medication nonadherence phenotypes, highlighting the differences in underlying behaviors and barriers that exist at the patient level…” “Each medication nonadherence phenotype requires different diagnostic tools and treatments…” The mechanistic jargon proceeds relentlessly: find out the adherential fault your patient suffers from, and take correctional action. Personally I think most “nonadherence” is due to a failure to gain the patient’s trust and understanding in the first place: perhaps we’d do better by examining some “health professional non-communication phenotypes” and correcting them with education about shared decision making.

2139 Oh boy, what exactly does it take to get a Preliminary Report into JAMA? On the showing of this one—you can read it in full—it’s a six week intervention for something that can’t really be defined or measured without stress testing. The intervention is escitalopram (the entaniomer of citalopram) and the “disease” is mental stress induced myocardial ischaemia. The outcome measure was not symptomatic—because the patients’ symptoms were already controlled with ß-blockers—but ischaemic change on an exercise test performed after a mentally stressful activity performed without ß-blockade. Those on escitalopram showed a bit less of this. I just don’t get it. It’s not even as if it was a drug company trial to market escitalopram. I don’t know what it was for.

2111 Oxygen therapy for very premature babies has been investigated for over 50 years, and I thought we knew as much as we were ever likely to about it. But here comes another trial aimed at determining the best target arterial oxygen saturation in very preterm infants—and it shows no difference in outcomes whether you aim for sats of 85-89% or 91-95%.

NEJM 23 May 2013 Vol 368
1963 Outcomes in cystic fibrosis continue to improve year on year, and a gene based cure is no longer an impossible mirage; but in the meantime, kids with CF continue to develop lung damage at varying rates from the age of 10 weeks onwards. An Australian study finds that the rate of development of bronchiectasis is closely associated with the neutrophil elastase activity measured in bronchoalveolar lavage fluid sampled at 3 months. It’s not a nice test to have to perform on little babies, but I guess if it helps to guide future therapy, it’s worth it.

1980 I make high demands of any screening procedure: a reduction in all cause-mortality is my gold standard. That is a statistical tall order, but at least there should be a robust reduction in younger deaths, and hence in life years gained. By such standards, low-dose CT lung scans for heavy smokers (depending on definition) do seem to cut the mustard. The latest figures come from 53,439 participants randomised to plain X ray or CT, and suggest “ that a reduction in mortality from lung cancer is achievable at US screening centers that have staff experienced in chest CT.” Nicely cautious wording.

1992 “Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family.” OK: you have 3 patients; that’s a good start. And the conclusion: “The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease.” Well, an unheard-of disease in a consanguineous family, anyway. More funding please?

2004 The “blocked pipes” metaphor for coronary heart disease is so embedded in our thinking that it’s quite a challenge to persuade people—even doctors—to realise that the most dangerous places in the coronary arteries are usually not the places which look narrowest on angiograms. On the contrary, the most likely places for acute ulceration and clot formation are the soft fatty uncalcified lesions that may not even cause much apparent stenosis. If only we had better methods for identifying them. You can read all about this—and much else—in a really helpful single-author update on mechanisms of acute coronary syndromes, which is well worth seeking out if you are not a subscriber.

Lancet 25 May 2013 Vol 381
1817 You don’t have to be an oncologist to have heard of CHOP chemotherapy, though you do if you are going to treat newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. This isn’t a particularly rare malignancy, accounting for a third of non-Hodgkin lymphoma, and this admirable trial managed to collect 1080 newly diagnosed patients and follow them up for 2 years after randomisation to either R-CHOP (rituximab plus CHOP) every 14 days or every 21 days. Never mind the detail: the fact is that the lighter regimen proved as good as the heavier, which has to be good news.

1827 For reasons I won’t try to explain, I have become keenly interested in the meta-analysis of individual patient data. Not that I would dream of trying it at home, which would be like trying to build a large hadron collider in the back garden. This is complex, grown-up stuff, and this one meta-analysis involved 15 centres spread across the USA, Italy, Australia and the UK. They analysed data for 83 399 women with 306 617 women-years of follow-up to determine the long-term effect of selective oestrogen receptor modulators (SERMs) on the incidence of breast cancer in high-risk women. The drugs used were tamoxifen, raloxifene, arzoxifene, and lasofoxifene, compared with placebo in all but one trial. The nine trials they examined are quite heterogeneous but a clear message emerges: “For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion.” There was an increase in thromboembolic events but a 34% protection from vertebral fracture. But despite all this painstaking work, the devil remains in the detail when making treatment long-term decisions for individual women.

1835 And now for one of those really weird phase 1 trials that the Lancetfrequently features. These things really baffle me, because if you look at the Lancet’s spin-off journals, you’ll find plenty of stuff worth reading by most generalists. Whereas this is a report of an experimental treatment used on nine Australians with nodular basal cell carcinoma of the skin. They all got various doses of Dz13 injected into their tumours, and none of them suffered any harm. “Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice.” There was some reduction in the size of five of the tumours. Since practically every white Australian over the age of 50 has at least one BCC, I wouldn’t advise anyone to wait until this treatment becomes more widely available. You’re better off trying kangaroo spit on the night of a full moon, or whatever else local tradition suggests. Then see a proper doctor and have the thing frozen or cut out.

BMJ 25 May 2013 Vol 346
This is the most shocking and shaming medical paper I’ve read for a long time: a survey of the gap in life expectancy for preventable physical illness in psychiatric patients. It comes from Western Australia, which presumably enjoys the same standards of psychiatric care as the rest of the rich world. “When using active prevalence of disorder (contact with services in previous five years), the life expectancy gap increased from 13.5 to 15.9 years for males and from 10.4 to 12.0 years for females between 1985 and 2005. Additionally, 77.7% of excess deaths were attributed to physical health conditions, including cardiovascular disease (29.9%) and cancer (13.5%). Suicide was the cause of 13.9% of excess deaths.” This is a scandal which needs urgent further investigation: are we becoming indifferent to physical illness and early death in the mentally ill? And are the newer drugs like olanzapine and quetiapine that we hand out so liberally actually contributing to an epidemic of cardiovascular disease in these patients?

Another depressing paper follows, though this is more for health service researchers and outcomes nerds. As a would be fledgling nerd of this feather, I had a touching faith that in the UK, the prevalence and incidence of major conditions like myocardial infarction could be determined accurately from a single database: unlike the USA, where there is a confusion of multiple agencies and registries. But the actual UK situation revealed in this paper is dreadful: look at the video abstract comparing data from the Clinical Practice Research Datalink (primary care data), Hospital Episode Statistics (hospital admissions), the disease registry MINAP (Myocardial Ischaemia National Audit Project), and the Office for National Statistics mortality register (cause specific mortality data). Minimal overlap! “Each data source missed a substantial proportion (25-50%) of myocardial infarction events. Failure to use linked electronic health records from primary care, hospital care, disease registry, and death certificates may lead to biased estimates of the incidence and outcome of myocardial infarction.” Phew! And I thought this was going to be easy. Maybe I should get digging that hadron collider in the garden after all.

A Dutch study investigating pneumonia in primary care uses chest radiography as the diagnostic gold standard. On that basis, absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever give an area under the ROC curve of 70%. If you add in a CRP>30, that improves to 77%. If you add in procalcitonin, nothing changes. But what does this actually mean? That you are going to withhold antibiotics until you can be more certain the patient has radiologically visible pneumonia? Or until she has a CRP in the target range? This study contributes to a literature which swings this way and that, but for me it has no lessons for clinical practice.

A few months ago, I commented on a perspective piece by Harlan Krumholz in the NEJM where he proposed the concept of a “post-hospital syndrome” of debility leading to repeated admission. This rings true in my own experience as a GP, and it is a concept taken up and expanded by hospital consultant Hugh McIntyre in a Personal View with the title “Admission to hospital could be considered a disease.” Everyone dealing with sick people needs to read this article and consider how it matches their own experience. Why do we send people to hospital? Is it because we expect the clever doctors to make some big improvement in their treatment, e.g. for heart failure? Do we expect patients to come out less frail, or more? How can we create a system which is more humane and less futile? Moving care into the community is not the answer, as an excellent editorial points out: we need a different structure of local hospital care.

Ann Intern Med 21 May 2013 Vol 158
709 Prostate cancer in elderly men is generally something they die with rather than die from, as we have all been taught for decades. A survey of 3183 American men with non-metastatic prostate cancer fleshes out this concept usefully. Overall it is certainly true, and the more comorbidity you suffer from, the higher is your chance that you will die from that rather than from prostate cancer: but for men with higher Gleason scores, and low morbidity scores, there may still be a place for aggressive early treatment.

727 If you have stable coronary artery disease, your choices lie between optimal medical therapy, percutaneous coronary intervention (which generally means drug-eluting stents these days) or coronary artery bypass surgery. As a certain number of cardiologists read these reviews, I will avoid entering this minefield and simply give you the conclusions of this study of 105 156 propensity score–matched Medicare patients aged 66 and over who were followed up between 1992 and 2008. “Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI.”

Soft pale yellow is always a delight in the garden, and just now the finest examples are provided by two plants: Paeonia mlokosewiczii and this lovely Trollius, a non-invasive buttercup with double flowers held high. It needs moisture and prefers part shade, and unfortunately differs from the common buttercup in that, when grown in such damp places, its leaves seem quite attractive to slugs and snails. Guard it carefully, with chemicals if you must, or with beer traps, or with punitive gastropod-hunting expeditions by torchlight.

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